We are following 50,844 US and Puerto Rican women who were between the ages of 35 and 74 and had a sister with breast cancer but did not have breast cancer themselves when they joined the study between 2003 and 2009. At enrollment, data on potential risk factors and current health status were collected using computer assisted telephone interviews and mailed questionnaires. Blood, urine, and environmental samples were collected in a home visit and banked for future use in nested studies of women who develop breast cancer (or other diseases) and a sample of those who don't. The cohort is tracked annually for changes in vital status and major health outcomes. Detailed follow-up questionnaires on health outcomes, environmental and lifestyle exposures, and special topics are completed every 2-3 years. Medical records and tumor tissue (for breast cancer cases) are retrieved for those who develop cancer or other conditions of interest. The first Sister Study follow-up survey was completed in June 2012; responses were obtained from 48,090 women for a response rate of 95%. The second detailed follow-up (January 2012 to 2014) is nearly complete with better than 90% response. The third comprehensive follow-up began recently. We are now collecting repeat biological and environmental samples from women diagnosed with breast cancer since enrollment and a random sample of the cohort. This will allow us to explore changes in biomarkers and exposures over time and in relation to breast cancer diagnosis and treatment. More than 2,000 women have reported a diagnosis of breast cancer or DCIS/LCIS. As expected, women in the cohort have, on average, twice the breast cancer risk as other US women. The ratio of observed to expected cases is greatest for women who also have a mother with breast cancer and for those whose sisters were younger at diagnosis. A novel finding is that risk differs for women with maternal versus paternal family history. Studies using baseline and follow-up data are exploring risk factors for breast cancer and other health conditions. We reported that early life socioeconomic adversity was related to increased risk for rheumatoid arthritis (RA). Current analyses are focusing on the impact of other early life factors, including farm residence and pesticides, and planning has begun for studies evaluating associations between breast cancer and autoimmune diseases and autoimmunity. In a study of urinary prostaglandin E2-metabolite (PGE-M) in 609 post-menopausal women (301 breast cancer cases and 308 subcohort members), several known pro- and anti-inflammatory factors were associated with urinary PGE-M, and post-menopausal breast cancer risk was increased with increasing levels of urinary PGE-M among women who did not regularly use non-steroidal anti-inflammatory drugs (NSAIDs). A related paper on fruit and vegetable intake is under review. These results support a role for prostaglandin E2 and inflammation in breast carcinogenesis, which may be modifiable by lifestyle and pharmacological interventions. We evaluated whether women at high risk for breast cancer were appropriately receiving tamoxifen therapy and explored factors associated with uptake and discontinuation of this treatment and found both under and over-use of this treatment in specific subgroups. Other recent work focuses on genetic variants, occupational organic solvent exposure, adiposity, and antibiotic use. We found that tubal ligation was associated with menopausal symptoms, but not with age at menopause or breast cancer risk. In an analysis of occupational exposures, we found that occupational solvent exposure was associated with increased risk for estrogen-receptor positive breast cancer and that risk was greatest for women exposed before a first full-term pregnancy a period of potentially enhanced susceptibility in breast tissue development. We are now analyzing data on risk associated with use of potentially endocrine disrupting chemicals and evaluating the potentially protective effect of occupational physical activity. We studied global DNA methylation and found a small but significant inverse association between LINE-1 and breast cancer. We also found that higher levels of physical activity were associated with increased LINE-1 methylation. We measured DNA methylation at over 27,000 CpG sites in baseline blood samples from 298 breast cancer cases and 612 non-cases and identified 250 CpGs that were differentially methylated between cases and non-cases, with 75% of these CpGs under-methylated in cases. Methylation data were better at predicting subsequent breast cancer risk than traditional measures such as Gail score, a measure that incorporates information on known breast cancer risk factors. We will soon have genome-wide SNP data for approximately 2,000 breast cancer cases and 2,000 non-cases and the same subgroup will also have data on 450,000 CpGs to evaluate methylation patterns in relation to breast cancer and in relation to exposures of interest. With co-investigators at the University of Washington, we geocoding participant addresses and linked these to information on air pollution levels. A paper on air pollution and asthma has recently been published and another on hypertension is under review. An analysis of air pollution and breast cancer is underway. A new collaboration has added data on residential proximity to green space (parks, forests, farm land) and land use patterns for future studies of neighborhood factors and breast cancer risk. Preliminary results link absence of green space to increased obesity prevalence. The Sister Study is collaborating with researchers from the Division of Cancer Prevention and Control at the Centers for Disease Control and Prevention (CDC) to study quality of life in breast cancer survivors. A survey of approximately 20,000 Sister Study participants in 2012 focused on the impact of having a sister with breast cancer. A second survey, completed in May 2013, involved women diagnosed with breast cancer and included topics that are of particular interest to younger women such as body image, work-life balance, and fertility as well as questions related to breast cancer care and quality of life. Together, these surveys will increase our understanding of the impact of cancer on the lives of breast cancer survivors and their families and provide information that will help identify factors related to healthy living after diagnosis. Current analyses focus on receipt of and satisfaction with prophylactic mastectomy, whether breast MRI is being used appropriately for high risk women, neurocognitive symptoms following chemotherapy, and behavioral change following breast cancer diagnosis. The Sister Study participates in the NCI-sponsored Cohort Consortium and has contributed cases a and data to studies of head and neck, gallbladder and ovarian cancers, allowing us to contribute to research on conditions we are not able to address on our own due to sample size constraints. We are taking the lead on a new Consortium project on pregnancy-associated breast cancer and co-directing a Consortium study on risk factors for pre-menopausal breast cancer. In the companion Two Sister Study we recently reported on associations between fertility drugs and menopause symptoms and breast cancer risk. Newer analyses concern risk factor differences for invasive and in situ disease and for breast cancer diagnosed before or after age 50. A submitted paper on migraines and breast cancer included data from both the Two Sister Study and the Sister Study, providing an example of how to pool data from cohort and case-control studies. See Weinberg Z01-ES04400.